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PubMed2004

Sequence context and modified hydrophobic moment plots help identify 'horizontal' surface helices in transmembrane protein structure prediction.

Transmembrane proteins make up at least one-fifth of the genome of most organisms and are critical components of key pathways for cell survival and interactions with the environment. The function of helices found at the membrane surface in transmembrane proteins has not been greatly explored, but it is likely that they play an ancillary role to membrane spanning helices and are analogous to the surface active helices of peripheral membrane proteins, being involved in: lipid association, membrane perturbation, transmembrane signal transduction and regulation, and transmembrane helical bundle formation. Due to the difficulties in obtaining high-resolution structural data for this class of proteins, structure-from-sequence predictive methods continue to be developed as a means to obtain structural models for these largely intractable systems. A simple but effective variant of the hydrophobic moment analysis of amino acid sequences is described here as part of a protocol for distinguishing helical sequences that are parallel to or 'horizontal' at the membrane bilayer/aqueous phase interface from helices that are membrane-embedded or located in extra-membranous domains. This protocol when tested on transmembrane spanning protein amino acid sequences not used in its development, was found to be 84-91% accurate when the results were compared to the partition locations in the corresponding structures determined by X-ray crystallography, and 72% accurate in determining which helices lie horizontal or near horizontal at the lipid interface.

Algorithms↗
PubMed2006

Preventing chondrocyte programmed cell death caused by iatrogenic injury.

Cartilage repair technology is advancing at a rapid pace. However, all techniques share a common weakness-unintentional chondrocyte cell death resulting from cartilage injury that occurs during preparation of the defect site. The loss of chondrocytes at the edge of host cartilage is likely to contribute to failed integration of regenerated tissue or grafts to the surrounding cartilage. Recent studies have demonstrated that "apoptosis", or programmed cell death (PCD), may be responsible for much of the cell death caused by cartilage injury. Theoretically, inhibitors of key pathways responsible for PCD could rescue chondrocytes and improve the results of cartilage repair surgery. The purpose of this study was to test the hypothesis that short-term, intra-articular PCD inhibitor treatment can limit chondrocyte death in vivo following simulated preparation of host cartilage for a repair procedure. A microcurette was used to create full-thickness articular cartilage injuries to the femoral condyles of adult New Zealand White rabbits. Animals received daily intra-articular injections either with a potent PCD inhibitor or with vehicle alone. Treatment with the inhibitor resulted in a significant reduction in the percentage of chondrocytes undergoing PCD compared to controls [treated=10.1+/-2.4%; controls=26.5+/-3.6%; (p=0.0013)]. These results provide proof of concept for the use of PCD inhibitors to enhance the results of cartilage repair surgeries.

Amino Acid Chloromethyl Ketones↗
PubMed2006

Ischemic vascular disease and solid cancers: opposing ends of the angiogenic spectrum?

Angiogenesis is a key pathway crucial to the patho-physiology of both vascular disease and solid cancer. In physiological conditions, a fine balance of pro- and anti-angiogenic factors is maintained as part of normal homeostatic mechanisms. It is widely accepted that excess angiogenesis influences the development or progression of tumours whilst insufficient angiogenesis may predispose to ischemic vascular disease. Although there are some factors, which predispose to both cancers and vascular disease, we believe there is a reasonable body of literature that suggests an inverse association between the two. We hypothesise that pro-angiogenic and anti-angiogenic phenotypes exist in the population. This may be due to a combination of underlying genetic variations and/or environmental factors. Pro-angiogenic phenotypes would have increased susceptibility to solid cancers and decreased predisposition to cardiovascular diseases and vice versa with the anti-angiogenic phenotypes. We propose that genetic and environmental factors causing a shift in the balance of angiogenesis will predispose individuals towards one group of pathologies while protecting them from another. Evaluation of this hypothesis will in the first instance involve carefully designed large population based observational studies to determine if an inverse relationship exists between the predisposition to ischemic vascular disease and the predisposition to solid cancer. Further detailed study of the pathways and underlying mechanisms of angiogenesis especially in disease states would facilitate better understanding of its regulation. Evaluation and validation of molecular markers that affect the 'angiogenesis pathway' may be helpful in determining the angiogenic potential of individual subjects. Determining where individuals lie along this spectrum may have a potential role in the prediction and stratification of risk of cancer and vascular disease. Modifying risk for patients at high risk of disease at the two opposing ends of the spectrum may then be possible by either lifestyle or dietary alterations or drugs targeting the angiogenic pathway.

Angiogenesis Inhibitors↗
PubMed2006

Prostaglandins and the colon cancer connection.

Colorectal cancer is a leading cause of cancer-related deaths throughout the world. Non-steroidal anti-inflammatory drugs (NSAIDs) are among the few agents that are known to inhibit colorectal tumorigenesis. The mechanisms that underlie this effect are poorly understood. Two recent studies have provided some significant insight. Castellone and colleagues showed that prostaglandin E2 modulates the beta-catenin signaling axis, a key pathway for colorectal tumorigenesis. Holla and colleagues showed that prostaglandin E2 might act via a nuclear receptor. These findings shed light on the mechanisms that underlie prostaglandin action, and provide a molecular framework for developing future treatments for colorectal cancer.

Adenomatous Polyposis Coli Protein↗
PubMed2006

Proteomic analysis of brain tissue from an Alzheimer's disease mouse model by two-dimensional difference gel electrophoresis.

We used a beta-amyloid precursor protein (APP) transgenic (Tg) mouse model that displays some of the typical Alzheimer-associated pathological features to study the brain proteoma associated with amyloid plaque deposition. Two groups (male and female) of 14-month-old Tg mice were compared with their wild type littermates. We used differential 2D electrophoresis coupled with mass spectrometry to generate one of the first complete image of changes in brain protein expression occurring in this well-recognized model of Alzheimer's disease (AD). We identified 15 different proteins, which are significantly regulated in this pathology (p<0.05, > or =1.5-fold variation in expression comparing with the wild type samples). These comprise a number of proteins that were already known to be implicated in AD and neurodegeneration, as well as several proteins which relationship with AD had not been shown before. Identified proteins were grouped according to their biological key pathways. Results obtained are discussed in view of existing bibliographic data on human AD transcriptoma and proteoma.

Alzheimer Disease↗
PubMed2004

The involvement of the blood-brain and the blood-cerebrospinal fluid barriers in the distribution of leptin into and out of the rat brain.

Leptin is a 16 kDa hormone that is produced by adipose tissue and has a central effect on food intake and energy homeostasis. The ability of leptin to cross the blood-brain and blood-cerebrospinal fluid (CSF) barriers and reach or leave the CNS was studied by the bilateral in situ brain perfusion and isolated incubated choroid plexus techniques in the rat. Brain perfusion results indicated that [(125)I]leptin reached the CNS at higher concentrations than the vascular marker, confirming that [(125)I]leptin crossed the brain barriers. Leptin distribution varied between CNS regions and indicated that the blood-brain barrier, in contrast to the blood-CSF route, was the key pathway for [(125)I]leptin to reach the brain. Further perfusion studies revealed that [(125)I]leptin movement into the arcuate nucleus, thalamus, frontal cortex, choroid plexuses and CSF was unaffected by unlabelled human or murine leptin at a concentration that reflects the upper human and rat plasma leptin concentration (2.5 nM). In contrast, the cerebellum uptake of [(125)I]leptin was decreased by 73% with 2.5 nM human leptin. Thus, this site of dense leptin receptor expression would be sensitive to physiological changes in leptin plasma concentrations. The highest rate (K(in)) of [(125)I]leptin uptake was into the choroid plexuses (307.7+/-68.0 microl/min/g); however, this was not reflected in the CSF (8.9+/-4.1 microl/min/g) and indicates that this tissue tightly regulates leptin distribution. The multiple-time brain uptake of [(125)I]leptin was non-linear and suggested leptin could also be removed from the CNS. Studies using the incubated rat choroid plexus model found that [(125)I]leptin could cross the apical membrane of the choroid plexus to leave the CSF. However, this movement was not sensitive to unlabelled human leptin or specific transport inhibitors/modulators (including probenecid, digoxin, deltorphin II, progesterone and indomethacin).This study supports the concept of brain-barrier regulation of leptin distribution to the CNS, and highlights an important link between leptin and the cerebellum.

Animals↗
PubMed2004

Enhanced expression of cytokines and chemokines by blood monocytes to in vitro lipopolysaccharide stimulation are associated with hostility and severity of depressive symptoms in healthy women.

The current study investigated the relation of hostility and severity of depressive symptoms, separately and jointly, to the capacity of blood monocytes to secrete an array of cytokines when stimulated by bacterial lipopolysaccharide (LPS). Subjects were 44 healthy, non-smoking, premenopausal women (aged 23-49 years) not currently taking oral contraceptives. Data were collected during the follicular phase of the menstrual cycle. The Cook-Medley Hostility (Ho) scale and the Beck Depression Inventory (BDI) were used to assess hostility and severity of depressive symptoms, respectively. Dual-color flow cytometry was used to measure the total expression of interleukin (IL)-1alpha, IL-1beta, IL-8, tumor necrosis factor (TNF)-alpha, monocyte chemotactic protein (MCP)-1 and monocyte inflammatory protein (MIP)-1alpha in blood monocytes following 4 h in vitro LPS stimulation of whole blood. In analyses adjusting for age, body mass index (BMI), fasting cholesterol, alcohol use, race and 17beta-estradiol (E(2)), higher Ho scores were associated with greater LPS-stimulated expression of IL-1alpha (beta = 0.033, p = 0.02), IL-8 (beta = 0.046, p = 0.01) and IL-1beta (beta = 0.024, p = 0.06). Higher BDI scores were associated with greater expression of TNF-alpha (beta = 0.042, p = 0.02) and IL-8 (beta = 0.045, p = 0.04). The linear combination of Ho and BDI scores was significantly associated with IL-1beta (beta = 0.18, p = 0.057), IL-8 (beta = 0.36, p = 0.01), TNF-alpha (beta = 0.25, p = 0.03), and IL-1alpha (beta = 0.18, p < 0.07). Thus, in healthy women, these psychological risk factors, alone and in combination, induce a proinflammatory phenotype in circulating monocytes characterized by the up-regulation of proinflammatory cytokines, supporting the hypothesis that inflammation may be a key pathway whereby hostility and depressive symptoms contribute to atherosclerosis and subsequent coronary heart disease (CHD).

Cells, Cultured↗
PubMed2006

Acetate kinase: not just a bacterial enzyme.

The bacterial enzymes acetate kinase (AK) and phosphotransacetylase (PTA) form a key pathway for synthesis of the central metabolic intermediate acetyl coenzyme A (acetyl-CoA) from acetate or for generation of ATP from excess acetyl-CoA. Putative AK genes have now been identified in some eukaryotic microbes. In Chlamydomonas reinhardtii and Phytophthora species, AK forms a pathway with PTA. AK has also been identified in non-yeast fungi but these fungi do not have PTA. Instead, AK forms a pathway with D-xylulose 5-phosphate phosphoketolase (XFP), a pathway that was also previously found only in bacteria. In Entamoeba histolytica, neither PTA nor XFP was found as a partner for AK. Thus, eukaryotic microbes seem to have incorporated the 'bacterial' enzyme AK into at least three different metabolic pathways.

Acetate Kinase↗
PubMedDate not supplied

Peroxisomes, lipid metabolism, and peroxisomal disorders.

Peroxisomes catalyse a large variety of different cellular functions of which most have to do with lipid metabolism. This paper deals with the role of peroxisomes in three key pathways of lipid metabolism, including: (1) etherphospholipid biosynthesis, (2) fatty acid beta-oxidation, and (3) fatty acid alpha-oxidation. Apart from a brief description of the peroxisomal enzymes involved in each of these pathways, the interaction between peroxisomes and other subcellular organelles, notably microsomes and peroxisomes, will be discussed. Finally, the current state of knowledge with respect to the different disorders of peroxisomal lipid metabolism will be described.

Acyl-CoA Oxidase↗
PubMed2003

Alzheimer's disease and total plasma aminothiols.

BACKGROUND: Plasma homocysteine is elevated in Alzheimer's disease, but little is known regarding levels of related aminothiols in the disease. We therefore determined total plasma homocysteine, cysteine, and glutathione levels in patients and control subjects and investigated their relationship with cognitive scores. METHODS: We performed a prospective, case-controlled survey based in two UK Psychogeriatric Assessment Centres. Fifty patients with features compatible with DSM-IV criteria for primary degenerative dementia of Alzheimer type were recruited together with 57 cognitively intact age- and gender-matched control subjects. Mini-Mental State and Alzheimer's Disease Assessment Scale-Cognitive Subsection (ADAS-Cog) scores were determined for patients and control subjects. Aminothiols were assayed with an automated high-performance liquid chromatography (HPLC) system. RESULTS: Patients had significantly elevated total plasma homocysteine (p <.001) and cysteine (p <.01), but there were no group differences for total plasma glutathione. Glutathione was, however, a highly significant and independent predictor of cognitive scores in patients (p =.002); lower plasma levels were associated with more severe cognitive impairment. CONCLUSIONS: Total plasma homocysteine and cysteine are elevated in Alzheimer's disease, suggesting intact transsulphuration but defective remethylation of homocysteine in the disease. Total plasma glutathione levels in patients correlate with cognitive scores. Taken together, these observations perhaps reflect the differential effects of Alzheimer's disease-related oxidative stress on the two key pathways of homocysteine metabolism.

Aged↗
PubMed2002

New therapies in sickle cell disease.

CONTEXT: New therapies have evolved from our improved understanding of the biology of sickle cell disease (SCD) and the availability of a useful transgenic animal model. Several therapeutic options are available that interrupt the sickling process at various key pathways. Nitric oxide (NO)is a critical factor in the pathophysiology of SCD and is a promising antisickling agent with vasodilation properties. NO regulates blood vessel tone, endothelial adhesion, and the severity of ischaemia-reperfusion injury and anaemia in SCD. Although NO is difficult to administer, its precursor, L-arginine, is an oral supplement. STARTING POINT: J R Romero and colleagues recently demonstrated in sickle transgenic mice that oral arginine supplementation induced NO production and reduced red-cell density by inhibiting the Gardos channel, which modulates cell hydration and polymerisation of haemoglobin S (Blood 2002; 99:1103-08). Haemoglobinopathies can be cured by stem-cell transplantation. This therapy is now accepted treatment in symptomatic children. However, most patients lack a genotypically identical family donor. G La Nasa and colleagues demonstrated unrelated-donor stem-cell transplantation may give similar results to related-donor stem-cell transplantation when extended phenotypic matching is used (Blood 2002; 99: 4350-56). This pilot study offers the possibility of cure to patients without a family donor. WHERE NEXT: Although potential opportunities to prevent morbidity in SCD through new therapies are exciting, most patients do not have access to standard multidisciplinary specialty care. Patients require both.

Anemia, Sickle Cell↗
PubMed1996

Role of rate-limiting enzymes of nucleotide metabolism in taurocholate-induced DNA synthesis inhibition.

BACKGROUND/AIMS: In previous studies we have shown the ability of bile acids to reduce the rate of thymidine incorporation into DNA by the regenerating rodent liver. The aim of the present work was to investigate the sensitivity of the key pathways involved in thymidine metabolism to taurocholate. METHODS/RESULTS: Incubation of [14C]-thymidine with mouse liver extracts revealed that addition of taurocholate to the reaction medium induced significant dose-dependent inhibition in the activity of the salvage nucleotide pathway rate-limiting enzyme, thymidine kinase, while other steps of nucleotide metabolism machinery, such as the rate-limiting enzyme of de novo deoxyribonucleotide synthesis, ribonucleotide reductase and the rate-limiting enzyme of thymidine catabolism, dihydropyrimidine dehydrogenase were found to be insensitive to inhibition by taurocholate. Additional experiments were carried out on isolated perfused rat livers whose regeneration was induced by two-thirds hepatectomy and synchronized by intravenous administration of reversible ribonucleic reductase inhibitor hydroxyurea (bolus: 170 mumol/100 g body weight, plus 10 h infusion: 2.0 mumol/min per 100 g body weight, from 14 to 24 h after hepatectomy). Hydroxyurea treatment was interrupted and liver perfusions were carried out 0, 2, 4 or 8 h later. Thymidine incorporation into DNA over 30 min perfusion with media containing [14C]-thymidine was measured after separating DNA from acid-soluble fraction. A marked increase in DNA synthesis was observed up to 4 h after stopping ribonucleotide reductase inhibition. At this time, reduced relevance of the salvage pathway can be expected as compared with the de novo released pathway. In contrast with the inhibitory effect observed when taurocholate was added to the perfusate of untreated regenerating livers, taurocholate was found to have no effect on DNA synthesis, at the peak of synchronized DNA synthesis, although taurocholate-induced alteration in thymidine metabolism was suggested from h.p.l.c. analysis of acid-soluble fraction. CONCLUSIONS: These results suggest that effects on the nucleotide metabolism machinery, and hence changes in deoxyribonucleotide phosphate pools may underlie the ability of taurocholate to affect DNA synthesis by the regenerating rodent liver.

Animals↗
PubMed2002

Physical activity increases the dissociation between subjective sleepiness and objective performance levels during extended wakefulness in human.

The process of heat loss has been shown to be a key pathway regulating sleepiness in humans. The influence of physical exercise with its attending heat production on subjective sleepiness and performance levels during total sleep deprivation (SD) was assessed in eight healthy young volunteers (mean age 21.1 years). Each subject participated in a SD cross-over study in which sleepiness and performance levels were tested under exercise and non-exercise conditions. The exercise entailed 15 min walking/h (3.0 Kcal/kg per h caloric consumption). Physical exercise significantly alleviated subjective sleepiness depending on the magnitude of the core body temperature elevation. This indicates that suppressing heat loss could prevent progression of subjective sleepiness during the nighttime. We found a strong positive correlation between increased sleepiness and decreased performance levels in each of the two experimental sessions. However, ANCOVA revealed a significant difference in the slope of the regression lines representing two sessions, indicating less subjective sleepiness with physical exercise despite the same decrease in performance. The present findings alert us to the possibility that increased physical activity during extended wakefulness could increase the dissociation between subjective evaluation of sleepiness and actual brain function, resulting in increased risk of human error.

Adult↗
PubMed2000

Protein phosphatases and the regulation of mitogen-activated protein kinase signalling.

The magnitude and duration of signalling through mitogen- and stress-activated kinases are critical determinants of biological effect. This reflects a balance between the activities of upstream activators and a complex regulatory network of protein phosphatases. These mitogen-activated protein kinase phosphatases include both dual-specificity (threonine/tyrosine) and tyrosine-specific enzymes, and recent evidence suggests that a single mitogen-activated protein kinase isoform may be acted upon by both classes of protein phosphatase. In both cases, substrate selectivity is determined by specific protein-protein interactions mediated through noncatalytic amino-terminal mitogen-activated protein kinase binding domains. Future challenges include the determination of exactly how this network of protein phosphatases interacts selectively with mitogen-activated protein kinase signalling complexes to achieve precise regulation of these key pathways in mammalian cells.

Animals↗
PubMed2024

Role of RNA G-Quadruplexes in the Japanese Encephalitis Virus Genome and Their Recognition as Prospective Antiviral Targets.

G-quadruplexes (GQs) have been primarily studied in the context of cancer and neurodegenerative pathologies. However, recent research has shifted focus to their existence and functional roles in viral genomes, revealing GQ-regulated key pathways in various human pathogenic viruses. While GQ structures have been reported in the genomes of emerging and re-emerging viruses, RNA viruses have been understudied compared to DNA viruses, including notable examples such as human immunodeficiency virus-1, hepatitis C virus, Ebola virus, Nipah virus, Zika virus, and SARS-CoV-2. The flavivirus family, comprising the Japanese encephalitis virus (JEV), poses a significant global threat due to recurring outbreaks yet lacks approved antivirals. In this study, we identified and characterized eight putative G-quadruplex-forming motifs within essential genes involved in genome replication, assembly, and internalization in the host cell, conserved across different JEV isolates. The formation and stability of these motifs were validated through a multitude of biophysical and cell-based assays. The interaction and binding affinity of these motifs with the known GQ-binding ligand BRACO-19 were supported by biophysical assays, confirming the capability of these motifs to form GQ structures. Notably, BRACO-19 also exerted antiviral properties through reduction of viral replication and infectious virus titers as well as inhibition of viral protein expression, as evaluated by the cell-based assays. This comprehensive molecular characterization of G-quadruplex structures within the JEV genome highlights their potential as promising antiviral targets for intervention strategies against JEV infection through GQ-specific ligands.

G-Quadruplexes↗
PubMed2003

Redox-photosensitized aminations of 1,2-benzo-1,3-cycloalkadienes, arylcyclopropanes, and quadricyclane with ammonia.

1,2,4-Triphenylbenzene and 2,2'-methylenedioxy-1,1'-binaphthalene successfully photosensitized the aminations of 1,2-benzo-1,3-cycloalkadienes, arylcyclopropanes, and quadricyclane with ammonia and primary amines in the presence of m- or p-dicyanobenzene, which gave the 4-amino-1,2-benzocycloalkenes, 3-amino-1-arylpropanes, and 7-amino-5-(p-cyanophenyl)bicyclo[2.2.1]hept-2-ene, respectively. A key pathway for the photosensitized amination is the hole transfer from the cation radicals of the sensitizers that were generated by photoinduced electron transfer to the electron acceptors to the substrates. Therefore, it was found that the relationships in oxidation potentials between the sensitizers and the substrates and the positive charge distribution of the cation radicals of the substrates were important factors for the efficient amination.

Journal Article↗
PubMed2000

Aspects of the biosynthesis of non-aromatic fungal polyketides by iterative polyketide synthases.

Lovastatin biosynthesis in Aspergillus terreus involves two unusual type I multifunctional polyketide syntheses (PKSs). Lovastatin nonaketide synthase (LNKS), the product of the lovB gene, is an iterative PKS that interacts with LovC, a putative enoyl reductase, to catalyze the 35 separate reactions in the biosynthesis of dihydromonacolin L, a lovastatin precursor. LNKS also displays Diels-Alderase activity in vitro. Lovastatin diketide synthase (LDKS) made by lovF, in contrast, acts non-iteratively like the bacterial modular PKSs to make (2R)-2-methylbutyric acid. Then, like LNKS, LDKS interacts closely with another protein, the LovD transesterase enzyme that catalyzes attachment of the 2-methylbutyric acid to monacolin J in the final step of the lovastatin pathway. Key features of the genes for these four enzymes and others, plus the regulatory and self-resistance factors involved in lovastatin production, are also described.

Anti-Bacterial Agents↗
PubMed2006

EGFR is phosphorylated at Ty845 in hepatocellular carcinoma.

Epidermal growth factor receptor (EGFR) is overexpressed in a significant proportion of hepatocellular carcinomas. Recent studies of EGFR inhibitors to treat hepatocellular carcinoma have been encouraging and better understanding of EGFR signaling may lead to more effective strategies for inhibiting this key pathway. The EGFR can be phosphorylated at different tyrosine sites, leading to subsequent activation of different pathways. Cell line and animal studies have shown that MAPK and STAT-3 are important mediators of the EGFR signal in liver cells. However, little is known about EGFR phosphorylation and subsequent signaling in primary hepatocellular carcinoma. We investigated the site of EGFR phosphorylation by Western blot in 18 hepatocellular carcinomas. Fourteen of 18 hepatocellular carcinomas had detectable EGFR by Western blotting and 13 of 14 showed phosphorylation at tyrosine 845. In contrast, no EGFR phosphorylation was detected at tyrosine 998, tyrosine 1045, or tyrosine 1068, which signal through other pathways including STAT-3 and MAPK. These findings were further explored by examination of EGFR expression and signaling pathway activation in tissue arrays comprised of 73 hepatocellular carcinomas using antibodies that recognize phosphorylated (or activated) proteins. Tissue array studies also found no correlation between EGFR expression (29% of cases) and STAT-3 nuclear positivity (16%), AKT (4%), MAPK (3%), or STAT-5 (3%) positivity, all P>0.05. EGFR expression was correlated with hepatitis B infection, but not with tumor size, nuclear grade, or proliferative rate. We conclude that EGFR is phosphorylated at tyrosine 845 in most hepatocellular carcinomas and that EGFR expression by immunohistochemistry does not correlate well with STAT-3, STAT-5, MAPK, or AKT immunostaining.

Adolescent↗